Morphine-6-glucoronide: A potent stimulator of locomotor activity in mice

Mørland, Jörg; Jones, Brenda L.; Palomares, Martha L.; Alkana, Ronald L.

doi:10.1016/0024-3205(94)00493-5

Cited by 25 publications

(9 citation statements)

References 15 publications

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“…Morphine and M6G have been shown to induce a dose-dependent increase in the locomotor activity of mice with broadly similar potency. 124 In a study with the d-receptor selective antagonist, naltrindole, a more potent reduction in the hyperlocomotion induced by M6G than that induced by morphine was shown, supporting the in vitro finding of a higher affinity of M6G than morphine for d-receptor sites. 122 The d-receptor (combined with the m-receptor), therefore, may play a greater role in M6G actions than in those of morphine.…”

Section: A C T I V I T Y a T J -A N D D -O P I O I D R E C E P T O R Ssupporting

confidence: 55%

Morphine‐6‐glucuronide: Actions and mechanisms

Kilpatrick¹,

Smith²

2005

Medicinal Research Reviews

128

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Morphine-6-glucuronide (M6G) appears to show equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the micro-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-opioid receptor, (3) M6G has a lower affinity for the kappa-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in pain and those involved in nausea, vomiting, and respiratory control or whether micro-opioid receptors in these brain areas differ in either their regulation or pharmacology.

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Section: A C T I V I T Y a T J -A N D D -O P I O I D R E C E P T O R Ssupporting

confidence: 55%

Morphine‐6‐glucuronide: Actions and mechanisms

Kilpatrick¹,

Smith²

2005

Medicinal Research Reviews

128

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“…In rodents, striatal dopamine release after opioid injection produces psychomotor stimulation, which is commonly used as a behavioral measure for opioid reward (Beninger, 1983;Wise and Bozarth, 1987;Mørland et al, 1994;Fields and Margolis, 2015). Here, we report a considerable reduction in locomotor activity and 6-MAM levels in brain tissue after both heroin and 6-MAM administration in mAb-pretreated mice.…”

Section: Discussionmentioning

confidence: 62%

“…6-MAM is further metabolized to morphine, which is ultimately glucuronidated into the pharmacologically inactive morphine-3-glucuronide (M3G), and the pharmacologically active morphine-6-glucuronide. The latter is normally not found in significant quantities in rodents (Mørland et al, 1994;Milne et al, 1996;Grung et al, 1998).…”

Section: Introductionmentioning

confidence: 96%

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

Kvello¹,

Andersen²,

Øiestad³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Immunotherapy can provide a supplemental treatment strategy against heroin use on the principle of sequestering the active drug in the bloodstream, thereby reducing its distribution to the brain. Previous studies have shown that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the main mediator of acute heroin effects. The objective of the present study was to characterize the pharmacological potential of a monoclonal antibody against 6-MAM (anti-6-MAM mAb) to counteract the heroin response. The individual contributions from heroin and 6-MAM to heroin effects were also examined by pretreating mice with anti-6-MAM mAb (10-100 mg/kg) prior to either heroin or 6-MAM injection (1.25-2.5 mmol/kg). The opioid-induced behavioral response was assessed in a locomotor activity test, followed by opioid and antibody quantification in blood and brain tissue. Pretreatment with mAb caused a profound reduction of heroin-and 6-MAM-induced behavior, accompanied by correspondingly decreased levels of 6-MAM in brain tissue. mAb pretreatment was more efficient against 6-MAM injection than against heroin, leading to an almost complete blockade of 6-MAM-induced effects. mAb pretreatment was unable to block the immediate (5-minute) transport of active metabolites across the blood-brain barrier after heroin injection, indicating that heroin itself appears to enhance the immediate delivery of 6-MAM to the brain. The current study provides additional evidence that 6-MAM sequestration is crucial for counteracting the acute heroin response, and demonstrates the pharmacological potential of immunotherapy against heroin use.

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“…Administration of equivalent doses of heroin, 6MAM, and morphine showed strikingly different potential to affect locomotor activity, which in mice reflects the presence of active compounds in the brain (Mørland et al, 1994;Handal et al, 2002). Low doses of heroin (Յ5 mol/kg) or 6MAM (Յ15 mol/kg) made the mice run significantly more compared with mice given equimolar doses of morphine, indicating differences in the stimulating potential between the drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Locomotor activation is an acute behavioral response to opiate administration in mice (Mørland et al, 1994). This behavior has been linked to opiate receptor stimulation and is completely inhibited by opiate antagonists (Joyce and Iversen, 1979).…”

mentioning

confidence: 99%

Increased Locomotor Activity Induced by Heroin in Mice: Pharmacokinetic Demonstration of Heroin Acting as a Prodrug for the Mediator 6-Monoacetylmorphine in Vivo

Andersen

Ripel²,

Boix³

et al. 2009

J Pharmacol Exp Ther

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126

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We investigated the relative importance of heroin and its metabolites in eliciting a behavioral response in mice by studying the relationship between concentrations of heroin, 6-monoacetylmorphine (6MAM), and morphine in brain tissue and the effects on locomotor activity. Low doses (subcutaneous) of heroin (Յ5 mol/kg) or 6MAM (Յ15 mol/kg) made the mice run significantly more than mice given equimolar doses of morphine. There were no differences in the response between heroin and 6MAM, although we observed a shift to the left of the dose-response curve for the maximal response of heroin. The behavioral responses were abolished by pretreatment with 1 mg/kg naltrexone. Heroin was detected in brain tissue after injection, but the levels were low and its presence too shortlived to be responsible for the behavioral response observed.The concentration of 6MAM in brain tissue increased shortly after administration of both heroin and 6MAM and the concentration changes during the first hour roughly reflected the changes in locomotor activity. Both the maximal and the total concentration of 6MAM were higher after administration of heroin than after administration of 6MAM itself. The morphine concentration increased slowly after injection and could not explain the immediate behavioral response. In summary, the locomotor activity response after injection of heroin was mediated by 6MAM, which increased shortly after administration. Heroin acted as an effective prodrug. The concentration of morphine was too low to stimulate the immediate response observed but might have an effect on the later part of the heroin-induced behavioral response curve.

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Morphine-6-glucoronide: A potent stimulator of locomotor activity in mice

Cited by 25 publications

References 15 publications

Morphine‐6‐glucuronide: Actions and mechanisms

Morphine‐6‐glucuronide: Actions and mechanisms

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

Increased Locomotor Activity Induced by Heroin in Mice: Pharmacokinetic Demonstration of Heroin Acting as a Prodrug for the Mediator 6-Monoacetylmorphine in Vivo

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